US12570650B2ActiveUtilityA1
6-substituted pyridazine compounds as SMARCA2 and/or SMARCA4 degraders
Est. expiryAug 4, 2040(~14.1 yrs left)· nominal 20-yr term from priority
A61P 35/00A61K 31/501C07D 487/08C07D 417/14
45
PatentIndex Score
0
Cited by
27
References
27
Claims
Abstract
The present invention provides 6-substituted pyridazine compounds of formula (I) which are therapeutically useful as SMARCA2 and/or SMARCA4 degraders. These compounds are useful in the treatment and/or delaying progression of diseases or disorders dependent upon SMARCA2 and/or SMARCA4 in a subject. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer or a tautomer or a prodrug thereof.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula (I):
or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof;
wherein
A is 5- to 6-membered heteroarylenyl or 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are substituted with 1, 2 or 3 Ra substituents;
Ra is hydrogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino or cyano;
R 1 is halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, —COORb, —CON(Rb) 2 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups that independently are hydroxy, (C 1 -C 6 )alkoxy, halogen, alkyl, haloalkyl, amino, —ONa, —COORc and —OCORc;
Rb and Rc independently are hydrogen, (C 1 -C 6 )alkyl or amino(C 1 -C 6 )alkyl;
R 2 is hydrogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, halogen, (C 1 -Celalkoxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or cyano;
L is —O—(CH 2 )p-, —O—(CH 2 )p-O—, —NRx-(CH 2 )p-, —NRx-(CH 2 )p-O—, —NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, -(3- to 10-membered cycloalkylenyl)-(CRxRy)n-, -(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n- or —O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl are substituted with 1, 2 or 3 Rd substituents;
Rd, at each occurrence, is independently selected from hydrogen, hydroxy, halogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino and cyano;
Rx and Ry, at each occurrence, are independently selected from hydrogen, (C 1 -C 6 )alkyl and halogen;
M is M-1 or M-2:
wherein,
Z is 5- to 6-membered heteroarylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl and amino(C 2 -C 6 )alkynyl; wherein the aminoalkyl and amino(C 2 -C 6 )alkynyl are optionally substituted with 1 or 2 substituents selected from (C 1 -C 6 )alkyl and —COCH 3 ;
R 3 and R 8 independently are (C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or amino(C 1 -C 6 )alkyl;
R 4 and R 9 independently are hydrogen, (C 1 -C 6 )alkyl, hetero(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, —CO-amino(C 1 -C 6 )alkyl or (C 1 -C 6 )acyl;
wherein the alkyl is optionally substituted with —OCOR′ or —OP(O)(OR″) 2 ;
R′ and R″ are independently selected from hydrogen and (C 1 -C 6 )alkyl;
R 5 , R 6 , R 10 and R 11 independently are hydrogen, (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl-, —CONRuRv, (C 1 -C 6 )acyl, and —(C 1 -C 6 )alkyl-heterocycloalkyl; wherein the aminoalkyl and heterocycloalkyl are optionally substituted with 1 or 2 substituents selected from (C 1 -C 6 )alkyl and —COCH 3 ; or
R 5 and R 6 together combined with the C atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with (C 1 -C 6 )alkyl or —COCH 3 ; or R 10 and R 11 together combined with the C atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with (C 1 -C 6 )alkyl or —COCH 3 ;
Ru and Rv independently are hydrogen, alkyl, 4- to 6-membered cycloalkyl or 6-membered aryl;
R 7 and R 12 are thiazolyl substituted with (C 1 -C 6 )alkyl, hydroxy, amino or halo(C 1 -C 6 )alkyl;
p is an integer selected from 1, 2, 3 and 4; and
n is an integer selected from 0, 1, 2 and 3.
2 . The compound of claim 1 , wherein R 1 is halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and amino.
3 . The compound of claim 1 , wherein A is phenylenyl or 5- to 6-membered heteroarylenyl each substituted with 1 or 2 Ra substituents.
4 . The compound of claim 1 , wherein A is phenylenyl, furanylenyl, thienylenyl, pyrrolylenyl, imidazolylenyl, oxazolylenyl, isoxazolylenyl, thiazolylenyl, isothiazolylenyl, 1H-tetrazolylenyl, oxadiazolylenyl, triazolylenyl, pyrazolylenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl; wherein each group is substituted with 1 or 2 substituents that are hydrogen, hydroxy, hydroxy(C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino or cyano.
5 . The compound of claim 1 , wherein L is —O—(CH 2 )p-, —O—(CH 2 )p-O—, —NRx-(CH 2 )p-, —NRx-(CH 2 )p-O—, —NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or —O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the 3- to 10-membered cycloalkylenyl and the 3- to 10-membered heterocycloalkylenyl are substituted with 1 or 2 Rd substituents.
6 . The compound of claim 5 , wherein L is, —O—CH 2 —, —O—CH 2 CH 2 —, —O—CH 2 CH 2 CH 2 —, —O—CH 2 CH 2 CH 2 CH 2 —, —O—CH 2 O—, —O—CH 2 CH 2 —O—, —O—CH 2 CH 2 CH 2 —O—, —O—CH 2 CH 2 CH 2 CH 2 —O—, —NH—CH 2 —, —NH—CH 2 CH 2 —, —NH—CH 2 CH 2 CH 2 —, —NH—CH 2 CH 2 CH 2 CH 2 —, —N(CH 3 )—CH 2 —, —N(CH 3 )—CH 2 CH 2 —, —N(CH 3 )—CH 2 CH 2 CH 2 —, —N(CH 3 )—CH 2 CH 2 CH 2 CH 2 —, —NH—CH 2 —O—, —NH—CH 2 CH 2 —O—, —NH—CH 2 CH 2 CH 2 —O—, —NH—CH 2 CH 2 CH 2 CH 2 —O—, —N(CH 3 )—CH 2 —O—, —N(CH 3 )—CH 2 CH 2 —O—, —N(CH 3 )—CH 2 CH 2 CH 2 —O— or —N(CH 3 )—CH 2 CH 2 CH 2 CH 2 —O—, —NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or —O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-heterocycloalkylenyl; wherein the heterocycloalkylenyl is piperidinylenyl, piperazinylenyl, azetidinylenyl, pyrolidinylenyl, tetrahydropyridinylenyl, diazobicyclooctanylenyl, azabicyclooctanylenyl, azaspiroheptanylenyl, tetrahydropyranyl, tetrahydropyridazinylenyl, morpholinylenyl, thiomorpholinylenyl, 1,4-dioxanylenyl, dioxidothiomorpholinylenyl, oxapiperazinylenyl, oxapiperidinylenyl, tetrahydropyranylenyl, dihydropyranylenyl or dihydropyrimidinylenyl; or (3- to 10-membered cycloalkylenyl)-(CRxRv)n-; wherein the cycloalkylenyl is cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl or cycloheptylenyl.
7 . The compound of claim 1 , wherein M is M-1; wherein
R 3 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl; R 4 is hydrogen, (C 1 -C 6 )alkyl, hetero(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )acyl; R 5 and R 6 independently are hydrogen, (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or ((C 1 -C 6 )alkyl)aminoalkyl-; and R 7 is thiazolyl substituted with (C 1 -C 6 )alkyl.
8 . The compound of claim 1 , wherein M is M-2; wherein
Z is oxazolylenyl or isoxazolylenyl; R 8 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl; R 9 is hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or (C 1 -C 6 )acyl; R 10 and R 11 independently are hydrogen, (C 1 -C 6 ) alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or ((C 1 -C 6 )alkyl)aminoalkyl-; and R 12 is thiazolyl substituted with (C 1 -C 6 )alkyl.
9 . The compound of claim 1 , wherein the compound is of formula (IA):
10 . The compound of claim 9 , wherein R 1 is halogen, hydroxy, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and the heteroaryl are each optionally substituted with 1 or 2 groups independently selected from (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, halogen and halo(C 1 -C 6 )alkyl.
11 . The compound of claim 9 , wherein L is —O—(CH 2 )p-, —O—(CH 2 )p-O—, —NRx-(CH 2 )p-, —NRx-(CH 2 )p-O—, —NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or —O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-.
12 . The compound of claim 9 , wherein M is
13 . The compound of claim 9 , wherein
R 1 is —Cl, —OH,
wherein each ring is optionally substituted with 1, 2 or 3 groups independently selected from (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, halogen and halo(C 1 -C 6 )alkyl;
R 2 is hydrogen or halogen;
Ra is hydrogen or halogen;
L is —O—CH 2 CH 2 CH 2 —, —O—CH 2 CH 2 CH 2 CH 2 —, —O—CH 2 CH 2 —O—, —O—CH 2 CH 2 CH 2 —O—, —NH—CH 2 CH 2 CH 2 CH 2 —, —N(CH 3 )—CH 2 CH 2 —O—, —N(CH 3 )—CH 2 CH 2 CH 2 CH 2 —, —NH—CH 2 CH 2 —O—
wherein each ring is substituted with 1 or 2 Rd substituents;
M represents
14 . The compound of claim 1 , wherein the compound is of formula (IB):
15 . The compound of claim 14 , wherein R 1 is —Cl, —OH,
wherein each ring is optionally substituted with 1 or 2 groups independently selected from (C 1 -C 6 )alkyl, hydroxy and halogen.
16 . The compound of claim 14 , wherein L is —O—(CH 2 )p-, —O—(CH 2 )p-O—, —NRx-(CH 2 )p-, —NRx-(CH 2 )p-O—, —NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or —O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-.
17 . The compound of claim 14 , wherein
R 1 is —Cl, —OH,
wherein each ring is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy and halogen;
R 2 is hydrogen or halogen;
Ra is hydrogen or halogen;
L is —O—CH 2 CH 2 CH 2 —, —O—CH 2 CH 2 CH 2 CH 2 —, —O—CH 2 CH 2 —O—, —O—CH 2 CH 2 CH 2 —O—, —NH—CH 2 CH 2 CH 2 CH 2 —, —N(CH 3 )—CH 2 CH 2 —O—, —N(CH 3 )—CH 2 CH 2 CH 2 CH 2 —, —NH—CH 2 CH 2 —O—
wherein each ring is substituted with 1 or 2 Rd substituents;
R 3 is (C 1 -C 6 )alkyl;
R 4 is hydrogen or (C 1 -C 6 )alkyl;
R 5 is hydrogen;
R 6 is (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or ((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl-; and
R 7 is thiazolyl substituted with (C 1 -C 6 )alkyl.
18 . The compound of claim 1 , wherein the compound is of formula (IC):
wherein X 1 and X 2 independently are N or C.
19 . The compound of claim 6 , wherein
X 1 and X 2 independently are N or C; R 1 is —Cl, —OH,
wherein each ring is optionally substituted with 1 or 2 groups independently selected from (C 1 -C 6 )alkyl, hydroxy and halogen;
R 2 is hydrogen or halogen;
Ra is hydrogen or halogen;
Rd is hydrogen or hydroxy;
Rx is hydrogen;
Ry is hydrogen or (C 1 -C 6 )alkyl;
M is
n is 0, 1, 2 or 3.
20 . The compound of claim 1 , wherein the compound is of formula (ID)
21 . The compound of claim 20 , wherein
R 1 is halogen, hydroxy, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein, the aryl and heteroaryl are optionally substituted with hydroxy, halogen, Q-C 6 )alkyl or halo(C 1 -C 6 )alkyl; R 2 is hydrogen or halogen; Ra is hydrogen or halogen; Rd is hydrogen or hydroxy; R 3 is (C 1 -C 6 )alkyl, (C 1 -C 6 )acyl or halo(C 1 -C 6 )alkyl; R 4 is hydrogen or (C 1 -C 6 )alkyl; R 5 is hydrogen; R 6 is hydrogen, (C 1 -C 6 )alkyl, halogen, hydroxy(C 1 -C 6 )alkyl or ((C 1 -C 3 )alkyl)amino(C 1 -C 6 )alkyl-; R 7 is thiazolyl substituted with (C 1 -C 6 )alkyl; and n is 0, 1, 2 or 3.
22 . A compound, that is selected from
Compound
IUPAC
1
(2S,4R)-4-hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
2
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
3
(2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-
yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
4
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
5
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-
yl)pyridin-2-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-
1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
6
(2S,4R)-4-hydroxy-1-((S)-2-(2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-4-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
7
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
8
(2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-N-((S)-1-
(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
9
(2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(6-(1-methyl-1H-pyrazol-4-
yl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetamido)butanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
10
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)acetamido)-3,3-
dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
11
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
12
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-
methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
13
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-fluoro-2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
14
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)propanamido)-3,3-dimethylbutanoyl)-N-((S)-1-
(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
15
(2S,4R)-1-((S)-2-(2-(4-(2-fluoro-4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
16
N-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-
yl)-1-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidine-4-
carboxamide;
17
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)cyclohexyl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
18
(2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)cyclohexane-1-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-
1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
19
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenoxy)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-
(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
20
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
21
(2S,4R)-4-hydroxy-1-((S)-2-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)azetidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
22
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)pyrrolidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
23
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(3-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
24
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(8-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)acetamido)-3,3-
dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
25
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)-8-azabicyclo[3.2.1]octan-8-yl)acetamido)-3,3-
dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
26
(2S,4R)-1-((S)-2-(2-(4-(2-fluoro-4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
27
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-
yl)pyridin-2-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-
1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
28
2S,4R)-4-hydroxy-1-((2S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-N-((S)-1-
(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
29 (Isomer-1)
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-N-((S)-1-
(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
30 (Isomer-2)
(2S,4R)-4-hydroxy-1-((2S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-N-((S)-1-
(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
31
(2S,4R)-4-hydroxy-1-((S)-2-(2-(6-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)-2-azaspiro[3.3]heptan-2-yl)acetamido)-3,3-
dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
32
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-hydroxy-4-(4-(6-(2-
hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin-1-yl)acetamido)-3,3-
dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
33
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)-1H-pyrazol-1-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-
((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
34
(2S,4R)-4-hydroxy-1-((S)-2-(5-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenoxy)pentanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
35
(2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenoxy)butanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
36
(2S,4R)-4-hydroxy-1-((S)-2-(5-((4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)amino)pentanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
37
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-(difluoromethyl)phenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
38
(2S,4R)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(6-(quinolin-8-yl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)butanoyl)-4-hydroxy-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
39
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(1H-indol-7-yl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
40
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(benzofuran-7-yl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
41
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(1H-indazol-7-yl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-
N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-
carboxamide;
42
(2S,4R)-4-hydroxy-1-(2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
43
(2S,4R)-4-hydroxy-1-(2-(3-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenoxy)propoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-
methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
44
(2S,4R)-4-hydroxy-1-(2-(3-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)(methyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-
((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
45
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)amino)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-
((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
46
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)(methyl)amino)piperidin-1-yl)acetamido)-3,3-
dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
47
(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(4-(6-hydroxypyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
48
(2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)pyrrolidine-
2-carboxamide;
49
(2S,4R)-N-(2-(dimethylamino)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-
4-hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)pyrrolidine-
2-carboxamide; and
50
(2S,4R)-4-hydroxy-1-(2-(3-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-
yl)phenyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-
(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;
or pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
23 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof and a pharmaceutically acceptable carrier or excipient.
24 . A method for degrading a target protein comprising administering to a subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein the compound is effective for degrading the target protein, wherein the target protein is SMARCA2 or SMARCA4 or a combination thereof.
25 . A method for treating or delaying progression of a cancer dependent upon at least one of SMARCA2 or SMARCA4 in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
26 . The method of claim 25 , wherein the cancer is hematologic cancers, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.
27 . A method for inhibiting tumor growth in a subject afflicted with cancer in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 ; wherein the cancer is hematologic cancers, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer or Wilms' tumor.Cited by (0)
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